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Liraglutide attenuates obese-associated breast cancer cell proliferation via inhibiting PI3K/Akt/mTOR signaling
Alaa Alanteet1, Hala Attia1, Musaed Alfayez2
1Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Abstract:
This study aims to explore the anti-proliferative, pro-apoptotic, and anti-migration activities of liraglutide (LGT) in MCF-7 breast cancer (BC) cells in subjects with obesity, particularly its effects on the PI3K/Akt/mTOR/AMPK pathway. The role of AMPK/SIRT-1, an essential regulator of adipokine production, in the effect of LGT on the production of adipose-derived adipokine was also assessed. MCF-7 cells were incubated in conditioned medium (CM) generated from adipose-derived stem cells (ADSCs) of obese subjects. MCF-7 cells were then treated with LGT for 72 h. Anti-proliferative, pro-apoptotic, and anti-migration activities were investigated using alamarBlue, annexin V stain, and scratch assay, respectively. Protein levels of phosphorylated PI3K, p-Akt, p-mTOR, and p-AMPK were investigated using immunoblotting. Levels of adipokines in ADSCs were determined using RT-PCR before and after transfection of ADSCs using the specific small interference RNA sequences for AMPK and SIRT-1. LGT evoked anti-proliferative, apoptotic, and potential anti-migratory properties on MCF-7 cells incubated in CM from obese ADSCs and significantly mitigated the activity of the PI3K/Akt/mTOR survival pathway-but not AMPK-in MCF-7 cells. Furthermore, the anti-proliferative effects afforded by LGT were similar to those mediated by LY294002 (PI3K inhibitor) and rapamycin (mTOR inhibitor). Our results reveal that transfection of AMPK/SIRT-1 genes did not affect the beneficial role of LGT in the expression of adipokines in ADSCs. In conclusion, LGT elicits anti-proliferative, apoptotic, and anti-migratory effects on BC cells in obese conditions by suppressing the activity of survival pathways; however, this effect is independent of the AMPK/SIRT1 pathway in ADSCs or AMPK in BC cells.
Insights
Liraglutide (LGT) exhibits anti-proliferative and pro-apoptotic effects on breast cancer cells in obese individuals. This action suppresses survival pathways, independent of the AMPK/SIRT1 pathway.
Area of Science:
- Oncology
- Metabolic Syndrome
- Cell Biology
Background:
- Obesity is linked to increased breast cancer (BC) risk and progression.
- Adipose-derived stem cells (ADSCs) in obesity can influence BC cell behavior.
- Liraglutide (LGT) is a GLP-1 receptor agonist with potential anti-cancer properties.
Purpose of the Study:
- To investigate the effects of LGT on MCF-7 breast cancer cells cultured in a medium from obese ADSCs.
- To determine LGT's impact on cell proliferation, apoptosis, and migration.
- To explore LGT's influence on the PI3K/Akt/mTOR/AMPK pathway and adipokine production.
Main Methods:
- MCF-7 cells were cultured in conditioned medium (CM) from obese ADSCs and treated with LGT.
- Cell proliferation, apoptosis, and migration were assessed using alamarBlue, annexin V staining, and scratch assays.
- Protein levels of PI3K, Akt, mTOR, and AMPK were analyzed via immunoblotting; adipokine levels were measured using RT-PCR.
Main Results:
- LGT demonstrated anti-proliferative, pro-apoptotic, and anti-migratory effects on MCF-7 cells.
- LGT significantly inhibited the PI3K/Akt/mTOR survival pathway in MCF-7 cells.
- LGT's effects were independent of the AMPK/SIRT1 pathway in ADSCs or AMPK in BC cells.
Conclusions:
- LGT exerts anti-cancer effects on breast cancer cells in obese conditions by suppressing key survival pathways.
- The anti-proliferative and apoptotic effects of LGT are mediated through the PI3K/Akt/mTOR pathway.
- The study highlights LGT's potential as a therapeutic agent in obese patients with breast cancer, independent of AMPK/SIRT1 signaling.
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